A new kind of highly specific irreversible enzyme inactivator is applied to a study of the neuropharmacology of enzymes involved in neurotransmitter metabolism. These inhibitors called kcat inhibitors, require catalytic conversion by the target enzyme prior to inactivating it. The enzyme thus commits "suicide" with a specifically constructed substrate. The high specificity of these inhibitors enables the construction of models for molecular diseases. In this grant we apply these inhibitors to an in vitro and in vivo study of gamma-aminobutyric acid (GABA) transaminase, glutamate decarboxylase and DOPA decarboxylase and cysteine sulfinate decarboxylase. These inhibitors will be used in gabanergic tissue culture system and in vivo to construct "mutants" of these cells which cannot produce or over-produce their neurotransmitters. The effects of these lesions on neuronal survival and competent synapse formation will be studied. The radioactively labeled glutamate decarboxylase inhibitor will be used to selectively label gabanergic cells in culture and in mouse cerebellum. It is hoped that the use of this technique coupled with autoradiography will allow for the selective mapping of gabanergic neuronal convectivity.